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(such as post-operative pain). 44 When compared with
typical opioids such as oxycodone, tapentadol
improves the health-related quality of life and
functional outcomes of patients with chronic pain
due to osteoarthritis and low back pain
significantly. 42 In the 36-item Short Form Health
Survey, tapentadol showed significantly greater
improvements from baseline than oxycodone in
physical and mental component summary scores
and all subscale scores except general health. 45
In an exploratory study, both tapentadol and
oxycodone produced respiratory depression.
Tapentadol 100mg (but not 150mg) had a modest
respiratory advantage over oxycodone 20mg. 46
With regard to other adverse effects, again the
lower mu-opioid effect results in significantly fewer
gastrointestinal adverse events (nausea, vomiting
and constipation) compared with typical opioids
such as oxycodone 41 (for constipation even when
compared with the slow-release combination of
oxycodone/naloxone). 47 A network meta-analysis of
opioid analgesics for chronic pain identified
tapentadol as the opioid with the lowest incidence
of overall adverse events, including constipation,
and the lowest trial withdrawal rate. 48 Similarly,
after three months administration, testosterone
depression was less with tapentadol than with
oxycodone. 47 Data on the effect of tapentadol on
immune function are limited, but experimental data
show maintenance of splenic cytokines with acute
and chronic use. 49
Buprenorphine
Buprenorphine has a complex pharmacology. It is a
potent but partial agonist of the mu-opioid receptor,
showing a high affinity but low intrinsic activity and
slow dissociation (half-life 2–5 hours). 50–52 It also
displays kappa-receptor antagonism, 51 agonism at
the nociceptin or opioid-receptor-like 1 receptor 53
and antagonism at delta-opioid receptors.
Buprenorphine is widely used in a sublingual
preparation for treatment of pain, 54 but, in
particular, for opioid substitution in opioid
addiction. 55 Sublingual buprenorphine provides
similar analgesic efficacy to intramuscular or
intravenous morphine. 56 Due to its high potency and
lipophilicity, buprenorphine can be used through
transdermal delivery systems. 57 These have provided
equivalent analgesia to morphine, hydromorphone,
oxycodone, fentanyl and methadone. 53
In experimental settings, buprenorphine has
a ceiling effect for respiratory depression; 58,59
however, fatalities due to respiratory depression
have occurred 60 but none are reported with
transdermal buprenorphine in a data analysis from
US poison centres. 61 Buprenorphine seems to cause
less tolerance than typical opioids such as fentanyl, 62
has anti-hyperalgesic effects 63 and may attenuate
OIH 64 with less glia cell activation via toll-like
receptor 4. 65 In animal experiments, buprenorphine
seems to be less immunosuppressive. 66,67
Buprenorphine also causes less OPIAD than typical
opioids. 68 It is also less constipating as a transdermal
preparation than even transdermal fentanyl 52 and
causes less cognitive dysfunction than typical
opioids, 53 a possible explanation for its lower
fracture risk due to falls. 69
Buprenorphine, like all other opioids, is
associated with misuse and diversion, in particular
in its sublingual preparation, where it is used as
substitution therapy in an at-risk population. 70
Poison Control Centre data showed that the 7-day
transdermal patch had lower prescription-adjusted
rates of intentional abuse and suspected suicidal
intent than all typical opioids (morphine,
oxycodone, oxymorphone, methadone and
transdermal fentanyl) in the US. 61
Conclusions
Over the last 30 years, a number of analgesics have
been identified that have similar analgesic efficacy
to typical strong opioids such as morphine,
oxycodone and fentanyl but whose activity is not
mediated exclusively by the mu receptor. This has
resulted in the suggestion to refer to the newer
medications as ‘atypical opioids’.
This term currently describes buprenorphine,
tramadol and tapentadol and this separation is not
only pharmacologically important but also clinically
useful because these medications differ from the
typical opioids with regards to safety and
tolerability.
A recent attempt to characterise atypical opioids
introduces the term mu-load as the percent
contribution of the mu-opioid component to the
adverse effect magnitude relative to a pure/classical
mu-opioid at equianalgesic doses. 71 While typical
opioids have by definition a mu-load of 100%,
atypical opioids would have a mu-load <100%. As an
example, tapentadol, using respiratory depression
and constipation, has a mu-load ≤40%. 71 This concept
enables the objective quantification of atypical opioids
and thereby supports this new terminology.
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